The preparation of what were generically described as 2,4-diaminoquinazolines substituted with lower alkyl in the 5 or 6 position was disclosed more than 20 years ago (U.S. Pat. No. 2,945,859, issued July 19, 1960), and a limited number of such compounds were, in fact, prepared. The compounds prepared were described as antibacterial agents, and related compounds were subsequently shown to be bactericidal in an agricultural context (U.S. Pat. No. 3,541,212) and to be hypotensive agents (U.S. Pat. No. 3,663,706). It was later shown that the series of 2,4-diamino-5-methyl-6-alkylquinazolines are effective inhibitors of dihydrofolic reductase isolated from mycobacterium and were effective growth inhibitors for this bacterium. It was also demonstrated that the combination of these compounds with diaminodiphenyl sulfone (DDS) produced a synergistic effect in inhibiting growth of mycobacteria (DeGraw, J., et al, J Med Chem (1974) 17: 762-764). A review of this work in comparison with other compounds was published by Colwell, W. T., et al, in "Chemistry and Biology of Pteridines" (1979), Kisliuk/Brown, eds., Elsevier, North Holland Inc., pp 215-218.
More complex compounds of the 2,4-diaminoquinazoline series were studied for their activity against various fungi and yeast by others. Hariri, A. R., et al, Proc Soc Exp Biol Med (1976) 151: 173-176 showed that the complex derivative, 2,4-diamino-6-(2-(3,4-dichlorophenyl)acetamido)quinazoline, was active in vitro and in vivo against the encapsulated yeastlike fungus, Cryptococcus neoformans. Their work showed that while other quinazoline derivatives were known to have activity against eucaryotic parasites such as the Plasmodium species, this particular compound showed no activity against these parasites. The minimum inhibitory concentration (MIC) of the Hariri quinazoline compound was approximately 6-8 ug/ml with respect to C. neoformans.
Additional complex derivatives of 2,4-diaminoquinazoline, which contain either a fused pyrrole ring at the 5, 6-positions or a complex amino side-chain at the 6-position were shown to be active against various Candida species at MIC levels of 0.5-4 ug/ml Castaldo, R. A., et al Antimicrob Agents and Chemotherapy (1979) 15: 81-86. This activity was quite variable with respect to a total of 17 candidate isolates; and the compounds in the series showed great difference in levels of activity. Indeed, most of the compounds of the series were not particularly active, and it appeared that the nature of the substituent(s) at the 5 and 6 positions (all of which, furthermore, contained rings) was quite critical. One of the compounds, N-cyclopropylmethyl-5,6-pyrrolo-2,4-diaminoquinazoline, showed synergistic activity against Candida in the presence of sulfamethoxazole (SMX). None of these compounds of the 2,4-diaminoquinazoline series has found clinical use against yeast or fungal infections although there is considerable need for effective antifungals. The commonly used antifungals, ketoconazole and amphotericin B, have unmanageable and serious side effects.